ISSN:0899-0042    

DOI:10.1002/chir.530060202

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractDisseminated candidiasis, a devastating disease with high morbidity and mortality in immunosuppressed patients, is difficult to diagnose because of the protean nature of symptoms and the lack of rapid and reliable laboratory diagnostic procedures. The subject of this review is the status of gas chromatographic–mass spectrometric techniques for the determination of D‐arabitinol, a unique metabolite of pathogenicCandidaspecies, in serum and urine. The enantiomers are separated by chiral chromatography followed by specific and sensitive detection using chemical ionization and selected ion monitoring. Using D/L‐arabinitol ratios, instead of individual concentrations, eliminates the need for knowing the volume of samples and for calibration curves. A new filter paper technique requires only an unmeasured drop of whole blood (venous or finger/heel puncture) or urine; paper spots are mailable. Parallel determinations of D/L‐arabinitol ratios in serum and urine in normal subjects and cancer patients with both normal and increased D/L‐arabitinol ratios revealed constant (1.2–1.3 range) ratios of serum D/L‐arabitinol/urine D/L‐arabinitol for all populations studied. Analyzing two body fluids taken at the same time increases reliability by reducing false positives. © 1994

ISSN:0899-0042    

DOI:10.1002/chir.530060203

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractIon channels are pharmacological receptors with specific drug binding sites. These binding sites define specific structure–function relationships for the actions of drug classes. Interpretation of these structure–function relationships may be complex because of state‐dependent drug‐channel interactions. These state‐dependent interactions determine affinity and access of drug to binding sites and may result in both quantitative and qualitative changes in structure–function relationships including stereoselectivity. A channel‐active drug may exhibit antagonist or activator properties according to membrane potential and the stereoselectivity of interaction may also change with channel state. © 1994 W

ISSN:0899-0042    

DOI:10.1002/chir.530060204

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe development of chiral HPLC methods and isolation techniques within Zeneca Agrochemicals (formerly ICI Agrochemicals) is reviewed. The use of low temperature to improve chiral separations has been successfully applied to production analysis, but although useful for some compounds it is regrettably not a universal panacea for all poor separations. The need to isolate small quantities of individual enantiomers from new compounds for research evaluation has led us to devise a more universal and cheap chiral stationary phase (CSP) for Preparative‐LC. Joint academic research produced a CSP based on tartaric acid which was made commercially available and it was gratifying to find it was the only phase able to resolve a novel insecticide. However, as new CSPs emerged almost every month, our attention turned to using a universal chiral detector for analysis, rather than via separation of individual enantiomers. Diode laser‐based polarimeters offered the opportunity of cheap, sensitive chiroptical detectors for HPLC and the ability to move away from chiral columns in both research and production analysis. Jointly sponsored research with a university has successfully explored the versatility of chiroptical detectors in agrochemical and food analysis. Comparison of chiral SFC with chiral HPLC and an extensive evaluation of established and research agrochemicals on a wide range of commercial CSPs have led to a revised method development strategy. Current work with high load displacement chiral chromatography will be described as a potential means of isolating pure enantiomers from racemates. © 1994 Wiley‐Lis

ISSN:0899-0042    

DOI:10.1002/chir.530060205

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe rapid development of stereospecific analytical, synthetic, and preparative methods has profoundly changed the prospects for development and application of chiral medicinal products. This has induced regulatory agencies, e.g., in Canada, the EEC, Japan, and the United States, to prepare guidance on this subject. The present draft documents are discussed, with emphasis on the two most important cases: (1) New racemates: How many extra requirements are justified? (2) Development of a single enantiomer from an approved racemate: how few are acceptable? At the moment the opportunities for early harmonisation are favourable and the formulation of one international guidance document seems feasible. © 1994 Wiley‐Liss, I

ISSN:0899-0042    

DOI:10.1002/chir.530060206

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractTrimetoquinol [1‐(3′,4′,5′‐trimethoxybenzyl)‐6,7‐dihydroxy‐1,2,3,4‐tetrahydroisoquinoline, TMQ] exists as two enantiomers, and the (−)‐(S)‐isomer is a potent β‐adrenergic receptor (β‐AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)‐ and (R)‐enantiomers of TMQ for interaction with β‐AR subtypes in tissues, membrane fractions, and cell systems. The isomeric‐activity ratios (IARs) of the TMQ isomers [(S)‐isomer ≫ (R)‐isomer]for stimulation of β1‐ and β2‐AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical β‐AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer β‐AR affinities were stereoselective for the (−)‐(S)‐isomer in membranes of guinea pig left ventricle (β1) and lung (β2) giving IARs of 115 and 389, respectively; and inE. coliexpressing human β1‐ and β2‐AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human β2‐AR and rat β3‐AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (−)‐(S)‐isomer of TMQ exhibits high affinity, and is a potent and highly stereoselective agonist for each β‐AR subtype, that the isomers generally fail to differentiate between the β‐AR subtypes, and that, based upon differences in IAR within β3‐AR containing systems, subtypes of

ISSN:0899-0042    

DOI:10.1002/chir.530060207

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe antidepressant fluoxetine (FLU) and its N‐demethylated metabolite, norfluoxetine (NFLU), each contains a chiral center. The combination of FLU and desipramine (DMI), another antidepressant, has been reported to be useful in treatment of depression, to dramatically increase plasma levels of DMI and also to produce more rapid β‐adrenergic receptor down‐regulation in brain than caused by DMI alone. We have now begun studies on the effects of this drug combination on the levels of FLU and NFLU enantiomers in the rat. In addition, the combination of FLU and iprindole (IPR) was also investigated. Male Sprague–Dawley rats were treated intraperitoneally with either normal saline vehicle, DMI (5 mg/kg/day), (R,S)‐FLU (10 mg/kg/day) or DMI (5 mg/kg/day) + (R,S)‐FLU (10 mg/kg/day) for 4 days. Following the last treatment, 24 h urine samples were collected. Rats were sacrificed and brains were removed. For the IPR study, rats were pretreated with either saline or IPR‐HCl (11.2 mg/kg) and then treated 1 h later with (R,S)‐FLU. After 5 h, the rats were sacrificed and brains were removed. Brain and urine samples were analyzed by gas chromatography with electron‐capture detection for free (R)‐ and (S)‐FLU and (R)‐ and (S)‐NFLU after extraction and reaction with (−)‐(S)‐N‐(trifluoroacetyl)prolyl chloride. The results from the brains of the rats treated with DMI/FLU indicate that levels of the enantiomers of both FLU and NFLU were significantly increased over those seen in the animals receiving (R,S)‐FLU alone. In the IPR/FLU treated rats, an increase in the brain levels of both (R)‐ and (S)‐FLU was noted when compared with rats receiving (R,S)‐FLU alone; however, there appeared to be no increase in the brain levels o

ISSN:0899-0042    

DOI:10.1002/chir.530060208

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe monoamine oxidase inhibitor pargyline (N‐benzyl‐N‐methyl‐2‐propynylamine) is known to undergo extensive in vitro microsomalN‐oxidation, thought to be mediated predominantly by the flavin‐containing monooxygenase (FMO) enzyme system. Formation of the pargylineN‐oxide (PNO) metabolite creates a chiral nitrogen centre and thus asymmetric oxidation is possible. This study describes a reverse‐phase high‐performance liquid chromatographic (HPLC) method for the quantitation of PNO and a chiral‐phase HPLC method for the determination of the enantiomeric ratio of PNO. In vitro microsomalN‐oxidation of pargyline was found to be highly steroselective in a number of species, with the (+)‐enantiomer being formed preferentially. This metabolic transformation was stereospecific when purified porcine hepatic FMO was used as the enzyme sourc

ISSN:0899-0042    

DOI:10.1002/chir.530060209

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractThe prochiral tertiary amineN‐ethyl‐N‐methylaniline (EMA) is known to be metabolicallyN‐oxygenated in vitro with microsomal preparations. This biotransformation is thought to be mediated predominantly by the flavin‐containing monooxygenase (FMO) enzyme system. MicrosomalN‐oxygenation of EMA is known to be stereoselective and varies between species. In order to further characterise this metabolic transformation, we have examined the in vitro metabolism of EMA using purified porcine hepatic FMO. Following incubation of EMA with purified FMO, EMAN‐oxide, the only metabolite detected, was found to be produced stereoselectively [ratio (−)‐(S):(+)‐(R), ca. 4:1]. The enantiomeric ratio of theN‐oxide product did not change markedly with respect to time, enzyme or substrate concentration. Determination of the kinetics of formation of theN‐oxide indicated a single affinity for the prochiral substrate with differential rates of formation of the enantiomers. The extent of EMAN‐oxide formation was shown to be affected by activators and inhibitors of FMO and pH, but its stereoselectively was unaltere

ISSN:0899-0042    

DOI:10.1002/chir.530060210

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY

摘要:

AbstractLifibrol, a new drug for the treatment of hypercholesterolemia, contains a stereogenic center bearing a secondary alcohol group. A normal‐phase achiral–chiral HPLC separation of the enantiomers of lifibrol and two of its metabolites was developed and validated for quantitation in dog plasma. A silica and a Chiralcel OD‐H column were operated in series and all six enantiomeric components and internal standard were directly separated. An initial solid‐phase extraction (phenyl) clean‐up step and a column‐switching step to eliminate late‐eluting compounds were also utilized. The solid‐phase extraction step was automated using a robotic system. Assay development, validation, and application of the method to a bioavailability study of the racemate and enantiomers of lifibrol in dogs are described. The lower limit of quantitation was 0.0125 μg/ml for each enantiomer of lifibrol using 200 μl of dog plasma with UV detection (255 nm). In dog plasma following oral or intravenous administration of the racemate, the (R)/(S) ratio of the enantiomers of lifibrol was greater than one and increased with time. Following administration of the individual enantiomers, chiral inversion of the (S)‐enantiomer but not the (R)‐enantiomer was observed.

ISSN:0899-0042    

DOI:10.1002/chir.530060211

出版商:Alan R. Liss, Inc.    

年代:1994

数据来源: WILEY